The present invention provides methods of treating pathological conditions, such as spasticity and convulsions, the symptoms of which are alleviated by a modulation of activity in the central nervous system (CNS), without producing undesirable excessive sedation or muscle weakness in animal subjects, including humans. More particularly, the invention relates to the therapeutic use of isovalerarnide, isovaleric acid, and related compounds in patients suffering from pathologies of this nature.
A number of pathological states, diseases, and disorders are characterized by a profound aberration in the normal function of the central nervous system (CNS). Such conditions include spasticity, strokes, spinal cord injuries, chronic neurodegenerative disorders and diseases such as Parkinson""s and Huntington""s diseases, Alzheimer""s disease, and epilepsy. At the clinical level, these states usually only respond to pharmacologic intervention with compounds or substances that possess significant activity at the level of the CNS.
Many agents currently employed in the treatment of pathologies such as spasticity and convulsions display troubling side-effect profiles which limit their long-term clinical utility. Among these agents, for example, are the benzodiazepines, which can cause impairment of cognition (impairment of memory-related performance, or xe2x80x9ccognitive bluntingxe2x80x9d). See, for example, ANTIEPILEPTIC DRUGS, Fourth Edition, (Levy et al, eds.), Raven Press, (1995). Two other clinically used agents are valproate and related therapeutically useful salts such as valproic acid hemisodium salt, which are hepatotoxic and teratogenic, and baclofen, which produces excessive muscle weakness and sedation. These side-effects severely limit the therapeutic potential for both drugs. It is apparent, therefore that improved and better-tolerated treatments for spasticity, convulsions, and other therapeutic indications are greatly to be desired.
Accordingly, it is an object of the present invention to provide a therapeutic approach for the treatment of various pathologies by effecting a modulation of CNS activity without producing excessive sedation, muscle weakness, fatigue, teratogenicity or hepatotoxicity.
It also is an object of the present invention to provide a method for alleviating one or more symptoms associated with a condition, such as spasticity, that is ameliorated by means of a centrally mediated decrease in muscle tone.
It is another object of the present invention to provide a novel anticonvulsant therapy.
It is another object of the present invention to provide a novel prophylactic therapy for migraine and other headache pathologies.
It is another object of the present invention to provide a novel therapy for affective mood disorders such as bipolar disorder.
It is another object of the present invention to provide a novel neuroprotective therapy.
It is another object of the present invention to provide a novel therapy to assist with substance withdrawal therapy and the substance cravings that often accompany such abuse.
In accomplishing these and other objectives, there has been provided, according to one aspect of the present invention, a method of using a compound selected from the group consisting of isovaleramide, a pharmaceutically acceptable ester of isovaleric acid, a pharmaceutically acceptable amide of isovaleric acid, and a compound selected from the group consisting of 2-methyl isovaleramide, 3-methylisovaleramide, 2,2-dimethylisovaleramide, 2,3-dimethylisovaleramide, 4-methylisovaleramide, 2,4-dimethylisovaleramide, 3,4-dimethylisovaleramide, 2,2,4-trimethylisovaleramide, 3-hydroxyisovaleramide, 4-hydroxyisovaleramide, 4-hydroxy-3-methyl-isovaleramide, 2-hydroxyisovaleramide, N-(2-acetamido)isovaleramide, 2-methyl-1-propyl sulfonamide, 1-methylethyl sulfamate, 2-methyl-1-propyl sulfamate, isopropyl carbamate, and isobutylcarbamate.
Thus, the present invention also provides a method of treatment comprising the step of administering, to a patient suffering from a pathology that is ameliorated by a modulation of CNS activity, a therapeutically effective amount of a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a composition selected from the aforementioned group of agents.
According to one embodiment of the invention, the pharmaceutically acceptable amide of isovaleric acid is selected from the group consisting of isovaleramide, N-ethyl isovaleramide, N-methyl isovaleramide, N,N-dimethyl isovaleramide, N-methyl,N-ethyl isovaleramide, N-(2-acetamido)isovaleramide (xe2x80x9cN-isovaleryl glycinamidexe2x80x9d), and N-isovaleryl GABA.
According to yet another embodiment of the invention, the treated pathology is an affective mood disorder, convulsions, a central neuropathic pain syndrome, a headache, or a restessness syndrome. In still another embodiment, the pathology is spasticity that is ameliorated by a centrally mediated decrease in muscle tone. In a further embodiment, the treated pathology is, a cerebral insult, neurodegeneration, or the acquisition of epilepsy. For still another embodiment, the treated pathology is substance abuse, craving of substance, addiction, and withdrawal.
In accordance with another aspect of the present invention, a method of use is provided for an extract of Valerianaceae, cramp bark, black haw, or hops in a method of treating a symptom of spasticity, where the extract comprises at least one compound that is hydrolyzed in vivo to yield isovaleric acid or isovaleramide. By the same token, the present invention provides a method for alleviating a symptom of spasticity in a subject in need of such treatment, comprising the step of administering a therapeutically effective amount of an extract as described above.
Other objects, features, and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the present invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.